Activation of both the complement and the contact systems of intrinsic coagulation are implicated in the pathophysiology of sepsis. C1-inhibitor (C1-INH) is a member of the superfamily of serine protease inhibitors (serpins) It is the major inhibitor of both factor XIIa and kallikrein of the contact system and also the only known inhibitor of activated C1s and C1r from the classical pathway of complement. Thus, C1-INH regulates the activity of two plasma cascade systems that form biologically active peptides, i.e. the anaphylatoxins C5a, C3a and C4a (the order corresponds to the relative activities), and bradykinin, which is known for its vasodilating and vasopermeability enhancing effects. Therefore C1-INH is a major regulator of inflammatory reactions. Preliminary data suggest that because C1-INH regulates activation of both cascade systems it has therapeutic potential for sepsis. Because C1-INH is inactivated by inflammatory proteases such as neutrophil elastase a protease resistant mutant C1-INH has been generated for therapeutic use. In phase l we will produce and purify sufficient quantities of this recombinant protease- resistant C1-INH (rPR-C1-INH) for animal studies. The activity of the rPR-C1-INH will be characterized using various in vitro assays and its activity will be determined in a rat model of endotoxemia. In Phase 11 we will produce sufficient quantities of rPR-C1-INH to evaluate efficacy in a primate sepsis model and begin preclinical development if primate studies are promising. This protease-resistant C1-INH has therapeutic potential for conditions associated with excessive activation of the contact and complement cascades such as bums, sepsis and ARDS. PROPOSED COMMERCIAL APPLICATION: A novel therapy for sepsis has significant commercial potential.